Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

Studies using omicsbased approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPAR alpha signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPAR alpha per se does not always explain the energetic state in the heart. The transcriptional activities of PPAR alpha are dynamic, yet highly coordinated. An additional level of complexity in the PPAR alpha regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPAR alpha regulatory mechanisms in cardiac metabolism and the possible role of PPAR alpha in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPAR alpha in the progression of cardiac hypertrophy and failure.